Tablets and capsules are generally unsuitable for administering high doses of biologically active ingredients since individual large dosage forms are difficult to swallow, or necessitate the administration of several tablets or capsules at a time, leading to impaired patient compliance. Chewable tablets are not ideal with young children and older people and are furthermore unsuitable for the incorporation of controlled-release coated pellets which can get crushed upon chewing.
Oral liquid suspensions of pharmaceutical and veterinary ingredients are designed primarily for those who experience difficulty in swallowing solid medication. However, they are not suitable for the incorporation of controlled-release particles into aqueous vehicles, since this often results in premature release of the biologically active ingredient into the suspending media during storage. Various efforts have been made to formulate sustained-release suspensions, the most successful using ion-exchange resins to bind charged molecules. Limitations of this system include low drug-loading capability and its applicability to only ionic drugs.
The formulation of a solid oral dosage form, whether tablet or capsule, which disintegrates rapidly in water to form an instantaneous homogenous suspension of adequate viscosity to be swallowed could circumvent the problems of administering large dosages without premature release from controlled-release particles while providing a ready measured dose. The key to the development of such a dosage form is a rapidly disintegrating tablet which disperses to form a viscous suspension. A delay in the development of a viscous gel is essential for achieving disintegration of the tablet. On the other hand, a rapidly increasing viscosity is necessary to provide adequate suspension properties.
The ideal solid oral dosage form should contain a swellable material which is able to increase viscosity on contact with water, at least one biologically active ingredient for immediate or sustained release delivery of the biologically active ingredient, and a filler conferring compactibility and the capability to disintegrate quickly. The inclusion of a viscosity increasing agent as a fine powder in the tablet matrix without any processing would interfere with disintegration and result in the formation of a voluminous hydrophilic mass which is impossible to disperse. Thus, it is necessary to incorporate such an agent into the tablet as granules or spheres so that the disintegration process occurs before the viscosity increase.
Hard gelatin capsules are well known in the art, especially as a pharmaceutical dosage form. Their sizes have been standard since the start of industrial manufacture their sizes, ranging from 5 (corresponding to a volume of 0.13 ml) up to 000 (volume of 1.36 ml). Thus, when a large amount of ingredient is required for each dosage unit, depending on the bulk density of the formulation, it may be necessary to use large size capsules which are not popular by the patients since thet are too large to swallow or, even worse, a size 000 capsule may be too small to receive the said amount. Beads and coated beads have often been filled into hard gelatin capsules to be used as conventional or controlled release dosage forms, however it is rather difficult to manufacture sustained-release formulations while using a hard gelatin capsule as the dosage form and such attempts have found relatively limited use despite efforts to improve the engineering of such formulations. This is why tablets are generally recognized as the most popular pharmaceutical oral dosage form participating in the comfort of the patient This is especially true of sustained-release tablets which are designed to release the drug slowly after ingestion In this case, patient compliance is improved since the daily number of tablets and the frequency with which the patient has to take these tablets to obtain the desired effect are considerably reduced. With sustained-release tablets, the drug's activity can be extended to take effect throughout the night, so that the patient need not be awakened until morning, thus resulting in time saving for nurses in hospitals.
The concept of tabletting coated biologically active ingredient particles is therefore of interest. Attempts have been made to produce tablets comprising microcapsules because of the known advantages of the latter: the microencapsulated substance is protected from external influences and vice-versa, for example stability is increased, chances of irritations or undesirable reactions with other components in a mixture are reduced or eliminated, unpleasant tastes and smells can be masked. However, compaction of coated beads for making tablets encounters difficult problems. If the beads have been coated by a rate-controlling polymeric cog to sustain biologically active ingredient delivery, cracking of the coating will cause the delivery system to change the rate of biologically active ingredient delivery or immediately release the dose. Preventing cracking of the coating is therefore of utmost importance. Large amounts of carriers have been found necessary m most cases in order to overcome the tendency of microcapsules or coated beads to brittleness by preventing their rupture on compression, thus resulting again in unacceptably large tablets.
The compaction of dry powders consists of two steps: (a) compression of the particulate solid followed by (b) bonding of the particles. The simplest and most frequent means to study the compaction process involves the relationship between punch force and tablet breaking strength i.e. the force required to break a tablet when subjected to a diametral load. Tablet tensile strength measured by diametral compression is also an appropriate parameter since it can be related by a simple equation to the applied lead, the tablet diameter and tablet thickness when a cylindrical tablet fails under tension by splitting cleanly into dimetral halves. One of the effects of powder compaction is an increase in the bulk density of the starting material. Quite often, the relationship between the applied pressure and density or porosity appears linear over the normal tabletting range of the applied pressure.
Compaction of shined release tablets containing coated pellets involves the following critical aspects. When such a dosage form is developed, the coated pellets must withstand the process of compaction without being damaged in order to prevent any undesirable effects on the biologically active ingredient release properties. The type and amount of coating agent, the size of the sub-unit, the selection of external additives having a cushioning effect, and the rate and magnitude of the applied pressure must be carefully considered. The process of bead compaction involves the application of stress to polymer-coated spherical cores. The desirable mechanical properties of coated beads to be compacted into a tablet together with excipients or placebo cushoning beads should be such that they are strong, not brittle and have low elastic resilience. The mechanical properties of both uncoated and coated beads were investigated by Aulton et al, supra who demonstrated that the presence of a film coat applied by means of an aqueous polymeric dispersion of polymethacrylates influenced the crushing strength and the elastic properties of beads: increasing the polymer loading has the effect of increasing the crushing strength of beads, whilst simultaneously enhancing bead resilience (characterized by a reduction in the elastic modulus).
Significant changes were observed between the compaction properties of the powder and pellet forms of the same formulations: the powder formulations deformed plastically and produced stronger compacts, whereas their pellet forms exhibited elastic deformation and brittle fragmentation, which resulted in compacts of lower tensile strength. It was also observed that the biologically active ingredient release rate from spheres coated with acrylate polymers increased with an initial increase in the applied pressure—this being attributed to the cracks in the coat that formed during compaction—but that further increases in pressure a retarded the release profile, possibly due to closer inter-particulate contacts within the tablet which partly compensated for the leaks of the pellet coats.
The selection of external additives is also of importance in the design of tablets since these additives are expected to prevent the occurrence of film cracking in the coated sub-units. Their compatibility with the biologically active ingredient-loaded pellets, in terms of particle size, is also very critical, since a non-uniform size distribution can cause segregation, resulting in tabletting problems such as weight variation, poor content uniformity, etc. For instance, placebo microspheres with good “compaction” and “cushioning” properties can be used as diluents. Alternatively, small-size biologically active ingredient-loaded pellets improve the content uniformity of low dose biologically active ingredients, however the surface area of pellets to be coated will increase as the size of the pellets deceases.
When using inert “cushioning” beads as diluents, good blending and minimal segregation is essential in order to achieve satisfactory uniformity of weight and content of the tablet dosage form Segregation is influenced by factors such as markedly different particle size, density or shape. In order to minimize the occurrence of segregation between the biologically active ingredient-loaded pellets and the inert diluent cushioning beads, it is deemed necessary to choose inert beads of the same size and approximately the same density as the active pellets. Further, the inert cushioning beads should be mechanically weaker than the coated biologically active ingredient-loaded ones.
Aulton et al, supra, tried to use different approaches to produce inert “cushioning” beads for cushioning of coated biologically active ingredient-loaded sustained action beads in order to prevent segregation due to size or density. Inert beads containing high microcrystalline cellulose levels, by virtue of the inherent bonding capacity of this material, were exceedingly hard. In addition, inert beads containing high lactose levels were also very hard. The replacement of all or part of the granulating water with isopropyl alcohol (in which lactose was insoluble) did not, as expected, enable the preparation of softer inert cushioning beads which would readily Went at low pressure during tabletting: the resulting beads were still too strong and required three times greater applied force than that of the biologically active ingredient-loaded beads before they crush. Thus, it was concluded that the admixture of biologically active ingredient-loaded beads and inert beads was not a viable proposition.
As noted above, conventional highly compactible fillers like microcrystalline cellulose can be mixed with biologically active ingredient-loaded beads and compressed into tablets. It is well known that beads made from microcrystalline cellulose, alone or in combination with brittle materials such as dicalcium phosphate or lactose, are very hard and not easily deformed or broken. However due to particle size differences with active ingredient-loaded beads, segregation occurs and results in weight variation and content uniformity problems. Microcrystalline cellulose granules produced by dry or wet granulation techniques and having similar size as the biologically active ingredient-loaded beads are able to minimize the segregation due to size differences and subsequent problems. However it was noted namely by Millili et al., Drug Dev.Ind.Pharm. 16(8):1411-1426 (1990) and by Aulton et al., Drug Dev.Ind.Pharm. 20(20):3069-3104 (1994) that such advantage is obtained to the detriment of compactibility. Therefore a need remains for filler beads which, when used in admixture with biologically active ingredient-loaded coated beads and compressed into tablets, will prevent cracking of the coating by keeping a high level of compactibility without giving rise to weight variation and active ingredient content uniformity problems due to segregation during compacting.
Hereinafter will be given a few specific examples of solutions provided in the prior art in order to attempt solving the various above problems. For instance, British patent No. 1,598,458 discloses successful tabletting of microencapsulated pharmacologically active substances having a brittle coating when a fine powder of a polyethylene glycol or another water-soluble natural or synthetic wax having a melting point from 30 to 100° C. is used as carrier in an amount from 2 to 20% by weight calculated on the brittle macrocapsules.
A first approach to produce improved tablets containing biologically active ingredient-loaded particles coated with a coating to sustain the biologically active ingredient action involves the use of flexible plastically deforming polymeric material which will deform under pressure when forming tablets while maintaining the integrity of the coating. For instance, EP-A-355,247 discloses that granules of a pharmaceutical composition, coated with a primary coating layer and optionally with a further protective coating, are compressed and molded together with non-coated components containing at least 10% by weight of non-swelling polymers having a high degree of compressability/moldability and a low degree of desintegration characteristic in order to prevent the destruction of the coating of the coated granules and to control or modulate the desintegration characteristic of the said coating. The non-swelling polymer may be polyvinylacetate, polyvinylchloride, polyethylene or an intestinally soluble polymer such as a cellulose derivative, a styrene-acrylic copolymer or the like. There is no particular limitation or restriction on the compound used as the coating of the coated granules, which among others may be a paraffin, a microcrystalline wax, a higher alcohol, a higher fatty acid or salt thereof, a higher fatty acid ester such as hydrogenated oil, camauba wax, beeswax, and the like. The coating material normally accounts for 1 to 80% by weight of the pharmaceutical composition. According to this document the coated granules may be produced by a conventional granulating method or by microencapsulation and it is also possible to formulate the active ingredient into the non-coated components.
Conventionally in the art, granules are aggregates formed by agglomeration (also referred to as granulation) of powder particles through the sticking together of individual feed material components. Although the said individual components may not segregate, the granules themselves may segregate if there is a wide size distribution. If this occurs in the tablet machines, products having large weight variations will result because these machines fill by volume rather than weight. This will lead to an unacceptable distribution of the biologically active ingredient content within the batch of finished product even though the said ingredient is evenly distributed by weight through the granules. Therefore there is a need for solving the inherent aforesaid disadvantages of granules.
As is well known in the art, beads (or pellets) are distinguishable from granules. Pelletization is an agglomeration process that converts fine powders or granules into small, free-flowing, spherical or semi-spherical units. As opposed to the process of granulation, the production of beads results in a narrow size-range distribution. The more spherical nature of beads compared to granules provides better flow and reduces segregation due to shape differences. Also, the surface morphology of beads is optimal for applying a functional coating.
Hence, a second approach to produce such sustained release tablets involves the mixing and compaction of biologically active ingredient-loaded beads with softer inert cushioning beads which deform at lower pressures during tabletting to prevent the fracture of the coated beads. For instance, WO 97/25029 discloses tablets containing (i) coated pellets of specific diameter and crushability comprising an active ingredient and preferably provided with controlled release properties, (ii) deformable pellets of specific diameter and crushability comprising a plastically deformable material having a melting point of no more man 70° C. such as an ester, ether or salt of a fatty acid having at least 12, preferably around 18 carbon atoms (suitably a glyceryl mono-, di- or triester of palmitic and/or stearic acid), further comprising 10 to 80% of a cellulosic derivative binder and further optionally comprising a water-insoluble inorganic powder diluent and (iii) pellets comprising a disintegrating component, preferably a water-insoluble inorganic salt. The pellets are used in a weight ratio active pellets: deformable pellets:disintegrating pellets in the range 1:(0.2-5.0): (0.2-5.0). In this document, the crushability of the deformable pellets is said to be important to achieve the protection or cushioning of the active pellets in the tabletting procedure. However alternatives solutions within this second approach have often failed. For instance the production of softer inert cushioning beads containing microcrystalline cellulose was not successful when water and/or alcohol was used as the granulating agent.
In order to overturn this difficulty, U.S. Pat. No. 5,780,055 discloses cushioning beads having a diameter of about 0.2 to 2.0 mm, prepared by extrusion-spheronization followed by freeze-drying and comprising microcrystalline cellulose optionally admixed with a disintegrant and/or a filler. The said beads are useful for making tablets when mixed with biologically active ingredient-loaded beads optionally coated with or containing a material for controlled or sustained release properties. The cushioning beads of this document are required to fragment initially into progeny primary powder particles followed by plastic deformation in order to held the tablet together by excipient-excipient contact. This prior art is thus limited to the use of a specific production technology, therefore a need remains for a technical solution to the above disclosed quality problems which can at the same time provide the industrial flexibility associated with the possibility to resort to various production technologies.
In summary, the formulation of ready-made suspensions containing-controlled release beads have been associated with premature leaching of the biologically active ingredient. The use of a dispersible tablet to form an instantaneous suspension can circumvent this problem together with the possibility of administering large doses of biologically active ingredients. The ideal tablet to form an instantaneous sustained release suspension should disintegrate quickly (less than 5 seconds) in water followed by the formation of a viscous suspension (within 1 to 2 minutes) to delay the settling of the biologically active ingredient-loaded membrane-coated beads until the dose is swallowed by the patient. In order to formulate this tablet three components are deemed to be necessary:    (1) biologically active ingredient-loaded membrane-coated beads intended to deliver the dose over a long period of time;    (2) a viscosity enhancer capable of delaying the sedimentation of the biologically active ingredient-loaded beads; and    (3) a filler system capable of producing mechanically strong compacts while protecting the biologically active ingredient-loaded beads from fracturing.
However none of the technical solutions available from the prior art provides the capability of solving the various above-mentioned problems at the same time. The present invention is based on the unexpected observation that the drawbacks of the prior art may be overcome while not requiring that the filler system initially fragment into progeny primary powder particles followed by plastic deformation in order to held the tablet together by excipient-excipient contact. The present invention therefore results from the selection of a cushioning bead meeting this condition